Abstract 601: Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival.

Abstract

Abstract Antioxidant-mediated stabilization of Nrf2 is known to up-regulate anti-apoptotic factors Bcl-2 and Bcl-xL that leads to reduced apoptosis and increased cell survival. In this report we investigated and found that anti-apoptotic factor Mcl-1 is coordinately induced with Bcl-2 and Bcl-xL factors in response to antioxidants. However, unlike Bcl-2 and Bcl-xL, Nrf2 did not control antioxidant-mediated up-regulation of Mcl-1. Further studies revealed that ERK1/2 phosphorylation of Mcl-1T163 primes Mcl-1 for phosphorylation by GSK3β at position S159. This modification degrades Mcl-1 and contributes to the maintenance of physiological level of Mcl-1 and cellular apoptosis. Exposure of Hep-G2 cells to antioxidant tert-butyl hydroquinone (t-BHQ) for 4-16h led to time dependent Akt-mediated inactivation of GSK3β, decreased Mcl-1S159 phosphorylation resulting in stabilization of Mcl-1 protein. Antioxidant-mediated increased Mcl-1 heterodimerized with Bim and Bax and down regulated cellular apoptosis. The contribution of antioxidant increased Mcl-1 in reduced apoptosis was further confirmed by siRNA-mediated inhibition of Mcl-1 that increased susceptibility to etoposide-mediated cell death and reduced cell survival through the activation of caspases 3/7. These results provided evidence that antioxidant control of GSK-3β led to increase in Mcl-1 that contributed to decreased apoptosis and increased cell survival. The results collectively suggest that antioxidant stabilized Nrf2 and GSK3β both through distinct mechanisms lead to increased anti-apoptotic factors Bcl-2, Bcl-xL and Mcl-1 that reduces apoptosis and promotes cell survival. Citation Format: Suryakant K. Niture, Anil K. Jaiswal. Antioxidant inhibition of GSK-3β stabilizes anti-apoptotic factor Mcl-1 leading to decreased apoptosis and increased cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 601. doi:10.1158/1538-7445.AM2013-601